The association of PTPN22 rs2476601 with juvenile idiopathic arthritis is specific to females.

A preponderance of females develop autoimmune disease, including juvenile idiopathic arthritis (JIA), yet the reason for this bias remains elusive. Evidence suggests that genetic risk of disease may be influenced by sex. PTPN22 rs2476601 is associated with JIA and numerous other autoimmune diseases, and has been reported to show female-specific association with type 1 diabetes. We performed main effect and sex-stratified association analyses to determine whether a sex-specific association exists in JIA. As expected, rs2476601 was associated with JIA in our discovery (413 cases and 690 controls) and replication (1008 cases and 9284 controls) samples. Discovery sample sex-stratified analyses demonstrated an association specifically in females (odds ratio (OR)=2.35, 95% confidence interval (CI)=1.52-3.63, P=0.00011) but not males (OR=0.91, 95% CI=0.52-1.60, P=0.75). This was similarly observed in the replication sample. There was evidence for genotype-by-sex interaction (Pinteraction=0.009). The association between rs2476601 and JIA appears restricted to females, partly accounting for the predominance of females with this disease.

Short-term treatment with a gonadotropin-releasing hormone antagonist, cetrorelix, in rheumatoid arthritis (AGRA): a randomized, double-blind, placebo-controlled study.

OBJECTIVES: Gonadotropin-releasing hormone (GnRH) stimulates immune responses; therefore, antagonizing GnRH with cetrorelix may have anti-inflammatory effects. The aim of this study was to assess short-term cetrorelix therapy in rheumatoid arthritis (RA) patients. METHOD: In this proof-of-concept, randomized, double-blind study involving 99 patients with active, long-standing RA, 48 patients received subcutaneous cetrorelix (5 mg/day on days 1 and 2; 3 mg/day on days 3-5) and 51 received placebo. The primary end-point was the change in the 28-joint Disease Activity Score based on C-reactive protein (DAS28-CRP) by day 5, when the greatest GnRH suppression was anticipated. Secondary end-points included the change in tumour necrosis factor (TNF)-α, and achievement of American College of Rheumatology (ACR) responses and DAS28-CRP < 2.6 by day 5. Patients were followed up on days 10 and 15. RESULTS: By day 5, DAS28-CRP was non-significantly reduced by 0.82 in the cetrorelix group compared to a 0.57 reduction in the placebo group (p = 0.091), TNF-α (log pg/mL) was significantly reduced in the cetrorelix group compared with the placebo group [0.55, 95% confidence interval (CI) 0.08-1.01, p = 0.023], and more patients on cetrorelix achieved ACR20 responses (40% vs. 18%, p = 0.015) and DAS28-CRP < 2.6 (13% vs. 0%, p = 0.009). Inflammatory markers increased towards baseline levels after withdrawal of treatment. Rates of adverse events were similar in both groups. CONCLUSIONS: Although there was no significant difference in the primary end-point between groups, antagonizing GnRH led to significant improvements in key secondary end-points. Thus, GnRH antagonists may have rapid anti-inflammatory effects in RA, already occurring within 5 days. The data suggest a novel mode of action for TNF-α inhibition in RA, and potentially in other autoimmune diseases.

CIITA gene variants are associated with rheumatoid arthritis in Scandinavian populations.

Expression of the major autoimmune risk loci DRB1 and DQB1 is regulated by the class II MHC (major histocompatibility complex) transactivator (CIITA), making the CIITA gene a strong autoimmune risk locus candidate. A CIITA promoter single-nucleotide polymorphism (SNP), rs3087456 (-168 A/G), has indeed been associated with several autoimmune diseases, including rheumatoid arthritis (RA). Recently, an intronic SNP rs8048002 has been suggested as a better susceptibility marker in Addison's disease. Therefore, we tested both SNPs in a panel of autoimmune diseases, consisting of Norwegian patients with RA (n=819), juvenile idiopathic arthritis (JIA; n=524), or type 1 diabetes (T1D; n=1211), and 2149 controls. We also included an independent Swedish RA cohort (n=2503) and controls (n=1416). Both rs3087456 and rs8048002 were significantly associated with RA (combined Norwegian and Swedish patients P(corrected)=0.012 and P(corrected)=0.0016, respectively), but not with JIA or T1D. Meta-analysis of 16 RA cohorts confirmed rs3087456 with only marginal significance (P=0.016). However, results were stronger in the Scandinavian subgroup (4 cohorts, P=3.8 × 10(-4)), indicating a population-dependent effect. A similar pattern was observed in a meta-analysis of rs8048002. Our results support involvement of CIITA in RA, but imply that this is population dependent and that the aetiological variant is yet to be discovered.

Anti-CCP and RF IgM: predictors of impaired endothelial function in rheumatoid arthritis patients.

OBJECTIVE: To determine whether the presence of anti-cyclic citrullinated peptide (anti-CCP) antibodies and rheumatoid factor immunoglobulin M (RF IgM) is associated with endothelial dysfunction in patients with rheumatoid arthritis (RA). METHODS: We studied the presence of anti-CCP antibodies and RF IgM and endothelial function in terms of the reactive hyperaemic index (RHI) in 53 consecutive RA patients. Endothelial function was measured by using a finger plethysmograph. RESULTS: RHI was significantly lower in anti-CCP-positive RA patients (n = 33, RHI = 1.78, SD = 0.30) than in anti-CCP-negative RA patients (n = 20, RHI = 2.19, SD = 0.59; p = 0.008). A similar result was found in RF IgM-positive patients (n = 34, RHI = 1.77, SD = 0.30) vs. RF IgM-negative patients (n = 19, RHI = 2.23, SD = 0.58; p = 0.003). There were no significant differences between the groups regarding age, gender, traditional cardiovascular risk markers, Disease Activity Score using 28 joint counts (DAS28), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), extra-articular manifestations (EAMs), use of glucocorticosteroids, statins, angiotensin-converting enzyme (ACE) inhibitors, and non-steroidal anti-inflammatory drugs (NSAIDs). CONCLUSION: The presence of anti-CCP antibodies and RF IgM was related to impaired endothelial function independent of other cardiovascular risk factors in RA patients. Thus, these autoantibodies might reflect an early reversible stage of the atherosclerotic process, and may indicate increased risk of cardiovascular disease (CVD). Further studies are needed to explore whether anti-CCP antibodies and RF IgM may act directly or indirectly to cause endothelial dysfunction, or merely reflect endothelial dysfunction in RA patients.

The association of luteinizing hormone and follicle-stimulating hormone with cytokines and markers of disease activity in rheumatoid arthritis: a case-control study.

OBJECTIVES: Disease activity in rheumatoid arthritis (RA) varies substantially during periods when luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels change, for example during pregnancy, postpartum, and menopause. We wanted to investigate whether small fluctuations in these hormones could be associated with similar fluctuations in cytokines and disease activity in RA. METHODS: Disease activity markers, serum LH, FSH, and 24 cytokines were assessed on days 1 and 8 in 20 RA patients (median age 58 years, six males) and 19 controls (median age 56 years, six males). RESULTS: Percentage changes in LH and FSH correlated positively with percentage changes in key proinflammatory cytokines such as tumour necrosis factor (TNF)alpha (LH r = 0.737, p = 0.0007; FSH r = 0.680, p = 0.001) and interleukin (IL)-1beta (LH r = 0.515, p = 0.050; FSH r = 0.749, p = 0.0008). Similar correlations were observed with IL-2, IL-2R, IL-8, monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and eotaxin, but not with the anti-inflammatory cytokine IL-10, in RA and not in controls. Percentage changes in LH, FSH, and cytokines were not correlated with percentage changes of several disease activity markers but were correlated positively with cross-sectional levels of disease activity markers [erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Visual Analogue Scale (VAS) pain, VAS global (physician/patient), and the modified Health Assessment Questionnaire (MHAQ)]. CONCLUSIONS: The significant associations between percentage changes in LH and FSH and percentage changes in key cytokines and several cross-sectional markers of disease activity may indicate that LH and FSH influence crucial points of the cytokine cascade in RA. This may help to explain, partially, why disease activity initiates or worsens during periods of increased LH and FSH, such as the postpartum period and the menopause.

Chest abnormalities in juvenile-onset mixed connective tissue disease: assessment with high-resolution computed tomography and pulmonary function tests.

BACKGROUND: Mixed connective tissue disease (MCTD) is associated with several chest manifestations. Only a few studies have focused on chest manifestations in juvenile-onset MCTD (jMCTD), and the true prevalence of pulmonary abnormalities on high-resolution computed tomography (HRCT) in these patients is unknown. PURPOSE: To investigate the occurrence of pulmonary abnormalities in jMCTD with particular reference to interstitial lung disease (ILD), and to evaluate a possible association between pulmonary findings and disease-related variables. MATERIAL AND METHODS: Twenty-four childhood-onset MCTD patients with median disease duration of 10.5 years (range 1-21 years) were investigated in a cross-sectional study by means of HRCT, pulmonary function tests (PFT), and clinical assessment. RESULTS: Discrete ILD was identified in six patients (25%). Median extent of ILD was 2.0%, and all except one of the patients had very mild disease in which 5% or less of the parenchyma was affected. The CT features of fibrosis were mainly microcystic and fine intralobular. The most frequently abnormal PFT was carbon monoxide uptake from the lung, which was abnormal in 33% of the patients. PFT and disease duration were not significantly associated with HRCT findings of ILD. CONCLUSION: The prevalence of ILD in childhood-onset MCTD patients was lower than previously believed. In most of the patients with ILD, the findings were subtle and without clinical correlation. The results suggest a low extent of ILD in childhood-onset MCTD, even after long-term disease duration.

Treatment of fibromyalgia at the Maharishi Ayurveda Health Centre in Norway. A six-month follow-up study.

BACKGROUND: Treatments offered at the Maharishi Ayurveda Health Centre in Norway are based on Maharishi Vedic medicine, which is also known as Maharishi Ayurveda. It is a consciousness based revival of the ancient Ayurvedic medicine tradition in India and is established by Maharishi Mahesh Yogi, the founder of the Transcendental Meditation (TM) technique. OBJECTIVE: To conduct a pilot study of the effect of the treatment program at the Health Centre on fibromyalgia patients. METHODS: Thirty-one women with diagnosed fibromyalgia received an individually designed Maharishi Vedic physiological purification therapy. All subjects received personal advice on diet based on Ayurvedic principles, including a novel approach to food into-lerance, and daily routines. In addition they were offered instruction in TM (for stress and pain management and personal development) (four subjects started), and recommended Ayurvedic herbal food products for home treatment. MAIN OUTCOME MEASURES: A modified Fibromyalgia Impact Questionnaire included a visual analogue scale for each of the seven outcomes: working ability, generalised pain, tiredness, stiffness, tiredness on arising, anxiety and depression. Pre-treatment scores were compared with scores at six-month follow-up for levels of statistical significance. RESULTS: Twenty-eight subjects (90%) completed the follow-up. The outcome measures were reduced by 25 to 46% by the study's endpoint: working ability (p<0.002), pain (p<0.001), tiredness (p<0.001), morning tiredness (p<0.001), stiffness (p<0.005), anxiety (p<0.136), and depression (p<0.001). A group of five excellent responders including all four participants who started to practise TM, had almost no symptoms by the endpoint. Compared to the non-meditating control group the TM-subgroup showed statistically significant improvements for all outcome measures except depression. CONCLUSIONS: In this pilot study fibromyalgia patients undergoing treatment at Maharishi Ayurveda Health Centre in Norway showed significant improvements six months post treatment. Because fibromyalgia is considered a treatment-resistant condition, these encouraging results warrant further research.

A coding polymorphism in NALP1 confers risk for autoimmune Addison's disease and type 1 diabetes.

Variants in the gene encoding NACHT leucine-rich-repeat protein 1 (NALP1), an important molecule in innate immunity, have recently been shown to confer risk for vitiligo and associated autoimmunity. We hypothesized that sequence variants in this gene may be involved in susceptibility to a wider spectrum of autoimmune diseases. Investigating large patient cohorts from six different autoimmune diseases, that is autoimmune Addison's disease (n=333), type 1 diabetes (n=1086), multiple sclerosis (n=502), rheumatoid arthritis (n=945), systemic lupus erythematosus (n=156) and juvenile idiopathic arthritis (n=505), against 3273 healthy controls, we analyzed four single nucleotide polymorphisms (SNPs) in NALP1. The major allele of the coding SNP rs12150220 revealed significant association with autoimmune Addison's disease compared with controls (OR=1.25, 95% CI: 1.06-1.49, P=0.007), and with type 1 diabetes (OR=1.15, 95% CI: 1.04-1.27, P=0.005). Trends toward the same associations were seen in rheumatoid arthritis, systemic lupus erythematosus and, although less obvious, multiple sclerosis. Patients with juvenile idiopathic arthritis did not show association with NALP1 gene variants. The results indicate that NALP1 and the innate immune system may be implicated in the pathogenesis of many autoimmune disorders, particularly organ-specific autoimmune diseases.

Spondyloarthritis: a strong predictor of early coronary artery bypass grafting.

OBJECTIVES: The main aim of the study was to examine whether patients with spondyloarthritides underwent their first coronary artery bypass grafting (CABG) at a younger age than those without spondyloarthritides. METHODS: Patients who underwent their first CABG at the Feiring Heart Clinic during 2001-2005 were preoperatively screened for spondyloarthritides, and the cardiological assessment was registered. We compared the characteristics of patients with and without spondyloarthritides. RESULTS: Of the 3852 patients undergoing their first CABG, 30 (0.78%) had spondyloarthritides. No statistically significant differences in traditional cardiovascular risk factors were found. The mean ages of patients with and without spondyloarthritides were 60.1 (SD = 8.7) and 66.9 (SD = 10.1) years, respectively. Spondyloarthritis was found by multivariate analysis to be a stronger independent predictor of early CABG than traditional cardiovascular risk factors [adjusted beta -6.2, p<0.001, 95% confidence interval (CI) -9.5 to -2.8]. Sixty per cent of spondyloarthritis patients and 52% of control patients had already suffered a myocardial infarction (p = 0.4). CONCLUSION: Spondyloarthritis was a stronger predictor of early CABG than most of the registered traditional cardiovascular risk factors. The prevalence of spondyloarthritis seemed to be higher in the CABG population than in the general population. These findings may indicate accelerated coronary artery disease (CAD) in spondyloarthritides.

The FCRL3 -169T>C polymorphism is associated with rheumatoid arthritis and shows suggestive evidence of involvement with juvenile idiopathic arthritis in a Scandinavian panel of autoimmune diseases.

BACKGROUND AND OBJECTIVES: The Fc receptor-like 3 (FCRL3) gene -169T>C single nucleotide polymorphism (SNP) has been reported to be associated with several autoimmune diseases (AIDs) in Japanese populations. However, association results in other populations have been conflicting. Therefore, we investigated this SNP in a Scandinavian panel of AIDs. METHODS: We genotyped patients with rheumatoid arthritis (RA; n = 708), juvenile idiopathic arthritis (JIA; n = 524), systemic lupus erythaematosus (SLE; n = 166), ulcerative colitis (UC; n = 335), primary sclerosing cholangitis (PSC; n = 365), Crohn disease (CD; n = 149), a healthy control group (n = 1030) and 425 trio families with type 1 diabetes (T1D). Statistical analysis consisted of case-control and family-based association tests. RESULTS: RA was associated with the C allele (odds ratio (OR) = 1.16, 95% CI 1.01 to 1.33) and the CC genotype (OR = 1.30, 95% CI 1.01 to 1.67) of the FCRL3 -169T>C SNP in our material. Suggestive evidence for association was also found for JIA (CC genotype: OR = 1.30, 95% CI 0.99 to 1.70), and clinical subgroup analysis indicated that this was connected to the polyarticular subgroup. No significant association was found with SLE, UC, CD, PSC or T1D. In patients with RA, we found no significant interaction between the FCRL3 -169T>C and PTPN22 1858C>T SNPs, nor between the FCRL3 -169CC genotype and IgM-rheumatoid factor or anti-cyclic citrullinated peptide titre levels. CONCLUSION: We found an association between the FCRL3 -169T>C SNP and RA, and suggestive evidence for involvement with JIA, in a Norwegian population. These findings lend support for a role for this SNP in RA across ethnically diverse populations, and warrant follow-up studies in JIA.

Everolimus in patients with rheumatoid arthritis receiving concomitant methotrexate: a 3-month, double-blind, randomised, placebo-controlled, parallel-group, proof-of-concept study.

OBJECTIVES: Everolimus, a proliferation signal inhibitor with disease-modifying properties, may be useful in treating rheumatoid arthritis (RA). This proof-of-concept study assessed efficacy and safety of everolimus in combination with methotrexate (MTX) in patients with refractory RA. METHODS: A multi-centre, randomised, double-blind, placebo-controlled trial was performed in 121 patients with active RA receiving MTX. Patients were randomised to receive everolimus (6 mg/day) or placebo. The primary endpoint was the American College of Rheumatology criteria for a 20% improvement in measures of disease activity (ACR20) at 12 weeks. RESULTS: There was a rapid onset of action and at 12 weeks the ACR20 response rate was significantly higher in the everolimus group (36.1%) than in the placebo group (16.7%; p = 0.022). Improvements from baseline in tender and swollen joint counts, patient's assessment of pain, and patient's and physician's global assessment of disease activity were significantly greater after treatment with everolimus. The most common adverse events (AEs) in the everolimus group were gastrointestinal (52.5% vs 31.7% in the placebo group), skin (29.5% vs 8.3%), and nervous system disorders (21.3% vs 10.0%); AEs leading to treatment discontinuation were reported for 16.4% and 10.0% of patients, respectively. Changes in haematological parameters, liver function tests, and lipid levels occurred more frequently with everolimus compared to placebo, but were mild and reversible. CONCLUSIONS: The study indicates that everolimus plus MTX provides clinical benefit with an acceptable safety and tolerability profile. It may offer a new treatment option in RA patients with inadequate response to MTX.

The PTPN22 promoter polymorphism -1123G>C association cannot be distinguished from the 1858C>T association in a Norwegian rheumatoid arthritis material.

The protein tyrosine phosphatase nonreceptor 22 (PTPN22) gene has, during the last 2 years, been recognized as a susceptibility gene for numerous autoimmune diseases, including rheumatoid arthritis (RA) and type 1 diabetes. An association between the exonic 1858C>T single nucleotide polymorphism (SNP) and RA has repeatedly been replicated in several Caucasian populations. The SNP is not associated with autoimmune diseases in Asian populations, as the 1858T allele is almost absent. Recently, a promoter polymorphism -1123G>C was proposed to be associated with acute-onset type 1 diabetes in Japanese and Korean populations. Furthermore, in Caucasian populations, the presence of additional PTPN22 risk variants has been suggested, indicating that the 1858C>T risk variant cannot explain the entire disease association observed in the region. In this study, we wanted to jointly address and integrate these separate findings to further elucidate the association between the PTPN22 gene and RA in a Norwegian material of 861 RA patients and 559 healthy controls. Our results revealed that the strength of the association with the PTPN22 promoter polymorphism, -1123G>C, is analogous to that observed for 1858C>T. As the -1123G>C variant is also polymorphic in Asian populations, our data underpin the need to further explore the association between this variant and autoimmune diseases in different populations.

Body composition, lipid and lipoprotein levels in childhood-onset systemic lupus erythematosus.

OBJECTIVES: Systemic inflammation, corticosteroid therapy, and reduced physical activity are risk factors for altered body composition in patients with systemic lupus erythematosus (SLE). The aim of this study was to assess whether body composition differs between childhood-onset SLE patients and healthy controls, and to investigate the impact of disease characteristics and lifestyle factors on body fat mass, serum lipids, and lipoproteins. METHODS: Fat mass and lean tissue mass were measured in a cross-sectional study of 68 childhood-onset SLE patients and 68 matched healthy controls by dual-energy X-ray absorptiometry (DXA). The influence of disease, glucocorticosteroids, disease activity and severity, physical activity, and dietary intake on fat mass was evaluated by multiple linear regression analysis. Serum lipid and lipoprotein levels were measured. RESULTS: Patients had a significantly higher fat mass [mean (SD) 35.3 (10.8) vs. 30.9 (11.1)%; p = 0.024] and lower lean mass [39.7 (9.8) vs. 44.4 (1.5) kg; p = 0.003] than controls. Corticosteroid use and the disease itself were significant independent predictors of greater fat mass, while disease activity, physical activity, and dietary intake had only a minor influence. Mean high density lipoprotein (HDL) cholesterol and apolipoprotein A1 (apo A1) levels were significantly lower (p<0.001), and the mean apo B/apo A1 ratio significantly higher (p = 0.004), in patients than in controls. CONCLUSION: Childhood-onset SLE patients had a higher fat mass and lower lean mass than healthy controls and corticosteroid use was an independent predictor of increased fat mass. Patients had a more proatherogenic lipid profile, which will contribute to the increased risk of coronary heart disease in SLE patients.

Pulmonary involvement in patients with childhood-onset systemic lupus erythematosus.

OBJECTIVE: Pulmonary involvement is a common finding in adults with systemic lupus erythematosus (SLE). The aim of this study was to investigate the frequency of pulmonary abnormalities in patients with childhood-onset SLE, with particular reference to interstitial lung disease (ILD), and to examine any association between pulmonary abnormalities and other disease-related variables. METHODS: A cohort of 60 Norwegian patients with childhood-onset SLE was examined in a cross-sectional study by high-resolution computed chest tomography (HRCT) and pulmonary function tests (PFT). Median disease duration was 11.2 years. Disease activity, cumulative organ damage and immunological markers were also assessed. RESULTS: Five patients (8%) had abnormal HRCT findings, including micronodules in four patients and bronchiectasis in one. None of the patients had radiographic evidence of ILD. PFT results were impaired in 37% of the patients, the most frequent pulmonary dysfunction was reduced carbon monoxide diffusing capacity (26%). HRCT findings, disease activity or serology did not correlate with PFTs. Reduced diffusion capacity was associated with smoking (p-value < 0.05). CONCLUSION: Lung function was moderately impaired, while the frequency of pulmonary parenchymal involvement was low. There was no radiographic evidence of ILD, which is an unexpected finding given the high frequencies reported in adult SLE patients assessed with HRCT. The results suggests that PFT values are often abnormal, but these are infrequently associated with development of ILD or other substantial parenchymal alterations in childhood-onset SLE, and do not require further HRCT investigation in asymptomatic patients.

Systemic lupus erythematosus and the extended major histocompatibility complex--evidence for several predisposing loci.

OBJECTIVE: Systemic lupus erythematosus (SLE) is an autoimmune disease reported to be associated with several alleles in the HLA complex. The purpose of this study was to systematically examine the extended HLA complex (xMHC) in order to get an overview of the primary predisposing genetic factors. MATERIALS AND METHODS: One hundred and sixty-four SLE patients and 254 healthy, unrelated controls were genotyped for HLA-DRB1, -B and -A alleles, as well as 13 microsatellites markers covering the xMHC. Moreover, we selected 335 additional controls matched with the patients for the HLA haplotypes showing the strongest associations, in order to look for additional predisposing loci. RESULTS: Two regions of the xMHC showed associations: the region covering DRB1 to B, and the extended class I region. Explicitly, DRB1*03 and B*08 displayed strong associations with SLE, which seem to be independent of each other. Furthermore, associations were seen with alleles at microsatellites D6S2225 and D6S2223, located about 3.6 Mb telomeric of HLA-B, and these were not secondary to the associations found with DRB1*03 and B*08. CONCLUSION: Both the DRB1*03 and the B*08 alleles display disease association, either implicating involvement of both alleles or caused by another yet unidentified gene(s) in linkage disequilibrium. The associations found in the extended class I region could be markers for a 'novel' predisposing locus (loci) in SLE, adding to the risk conferred by DRB1*03 and B*08. Interestingly, this region has been shown to also be associated with other autoimmune diseases, hence the gene(s) might confer a general propensity for autoimmunity.

Disease duration, hypertension and medication requirements are associated with organ damage in childhood-onset systemic lupus erythematosus.

OBJECTIVE: To investigate the frequency of organ damage in childhood-onset systemic lupus erythematosus (SLE) and to identify disease variables and patient characteristics related to organ damage. METHODS: A cohort of 71 patients was examined in a cross-sectional study after a mean disease duration of 10.8+/-8.2 years (mean age 26.4+/-9.8 years). The occurrence of organ damage was measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). Factors analysed as possible explanatory variables of organ damage were the following: demographic variables, clinical variables at diagnosis and during disease course, as well as medication use. Growth and self-reported health status were also measured. RESULTS: The most frequent areas of organ damage were in the neuropsychiatric (28%), renal (13%) and musculoskeletal (13%) organ systems. Forty-three patients (61%) had evidence of damage. The mean SDI score was 1.3 for the whole study population. Hypertension, longer disease duration and use of cyclophosphamide were factors significantly related to an increasing SDI score in multiple linear regression analyses. Furthermore, patients with damage (SDI > or =1) compared to those without damage (SDI = 0) had a significantly higher cumulative corticosteroid dose (24.7 g versus 10.6 g) and more frequently required high-dose prednisolone at diagnosis (68% versus 43%). CONCLUSION: Evidence of organ damage was found in 61% of all patients. Long disease duration, known hypertension and use of cylophosphamide were significantly associated with an increasing SDI score. Furthermore high-dose prednisolone at diagnosis and cumulative prednisolone dose were significantly related to the presence of organ damage.

Association analysis of the 1858C>T polymorphism in the PTPN22 gene in juvenile idiopathic arthritis and other autoimmune diseases.

A functional single nucleotide polymorphism, 1858C>T, in the PTPN22 gene, encoding a tyrosine phosphatase, has been reported to be associated with type I diabetes and some other autoimmune diseases. To further investigate whether this polymorphism may be a general susceptibility factor for autoimmunity, we performed an association study in five different autoimmune diseases, three previously not tested. We found an association with juvenile idiopathic arthritis (OR=1.41; P=0.04), not previously reported, and a tendency for an association with coeliac disease (OR=1.35; P=0.08). In primary sclerosing cholangitis, no association was observed (OR=0.95; P=0.8). Furthermore, we confirmed the increased risk in rheumatoid arthritis (OR=1.58; P=0.001), but could not find support for an association with systemic lupus erythematosus (OR=0.94; P=0.8). Altogether, we have provided further evidence of an association between autoimmune diseases and the 1858C>T polymorphism in PTPN22.

Genetic association between juvenile rheumatoid arthritis and polymorphism in the SH2D2A gene.

T-cell-specific adapter protein (TSAd) involved in the negative control of T-cell activation is encoded by the SH2D2A gene. Our recent studies indicate that homozygosity for short (ie GA(13) and GA(16)) alleles of the SH2D2A gene promoter is associated with development of multiple sclerosis. To study whether the same SH2D2A promoter polymorphism also contributes to the genetic susceptibility to develop juvenile rheumatoid arthritis (JRA), we examined 210 JRA patients and 558 healthy unrelated controls from Norway. The frequency of the short allele GA(13) was increased among the JRA patients compared to control (0.098 vs 0.05; P(n=8)=0.042). There was a significant increased frequency of HLA-DRB1(*)08-positive patients carrying two copies of 'short' alleles GA(13) and/or GA(16) compared to healthy controls (16% vs 6%; P(n=4)=0.016). Our data indicate that the 'short' alleles of the SH2D2A promoter could contribute to the genetic susceptibility to JRA.